Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling
Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling
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DOI：
10.1038/s41590-020-0641-5
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发表时间：
2020-03-30
影响因子：
30.5
通讯作者：
Fu, Yang-Xin
中科院分区：
文献类型：
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作者：
Han, Chuanhui;Liu, Zhida;Fu, Yang-Xin
治疗性照射可以触发DNA敏感通路并引发抗肿瘤免疫。Fu和他的同事证明，肿瘤可以利用内在的凋亡途径来避免辐射后免疫原性细胞死亡。高剂量辐射激活肿瘤细胞中的半胱天冬酶，产生大量的DNA片段，用于抗原呈递细胞中的DNA传感，但辐射后肿瘤细胞中的内在DNA传感相当有限。在这里，我们证明了辐射肿瘤细胞劫持半胱天冬酶9信号转导抑制内在的DNA传感。肿瘤来源的线粒体DNA触发内在DNA传感，而不是凋亡基因组DNA。具体而言，Casp 9（-/-）肿瘤中线粒体DNA传感的丧失消除了放射的增强的治疗效果。我们证明，emricasan，泛半胱天冬酶抑制剂，与辐射相结合产生协同治疗作用。此外，肿瘤细胞中CASP 9信号传导的丧失通过上调程序性死亡配体1（PD-L1）导致适应性抗性，并导致肿瘤复发。额外的抗PD-L1阻断可以进一步克服这种获得性免疫抗性。因此，将放射与半胱天冬酶抑制剂和抗PD-L1组合可以通过依次阻断内源性和外源性抑制信号传导来有效控制肿瘤。
Therapeutic irradiation can trigger DNA-sensing pathways and trigger antitumor immunity. Fu and colleagues demonstrate that tumors can co-opt intrinsic apoptotic pathways to avoid immunogenic cell death following irradiation.High-dose radiation activates caspases in tumor cells to produce abundant DNA fragments for DNA sensing in antigen-presenting cells, but the intrinsic DNA sensing in tumor cells after radiation is rather limited. Here we demonstrate that irradiated tumor cells hijack caspase 9 signaling to suppress intrinsic DNA sensing. Instead of apoptotic genomic DNA, tumor-derived mitochondrial DNA triggers intrinsic DNA sensing. Specifically, loss of mitochondrial DNA sensing in Casp9(-/-) tumors abolishes the enhanced therapeutic effect of radiation. We demonstrated that combining emricasan, a pan-caspase inhibitor, with radiation generates synergistic therapeutic effects. Moreover, loss of CASP9 signaling in tumor cells led to adaptive resistance by upregulating programmed death-ligand 1 (PD-L1) and resulted in tumor relapse. Additional anti-PD-L1 blockade can further overcome this acquired immune resistance. Therefore, combining radiation with a caspase inhibitor and anti-PD-L1 can effectively control tumors by sequentially blocking both intrinsic and extrinsic inhibitory signaling.